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MINISTRY OF HEALTH OF VIETNAM
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SOCIALIST REPUBLIC OF VIETNAM
Independence - Freedom – Happiness
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No. 07/2022/TT-BYT
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Hanoi, September 05, 2022
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CIRCULAR
ON PHAMARCEUTICAL PRODUCTS FOR
WHICH IN VIVO BIOEQUIVALENCE STUDIES ARE REQUIRED AND REQUIREMENTS FOR
DOCUMENTATION OF BIOEQUIVALENCE STUDY REPORTING DURING APPLICATION FOR
MARKETING AUTHORIZATION OF THESE DRUGS IN VIETNAM
Pursuant to the Law on
Pharmacy dated April 06, 2016;
Pursuant to Decree No.
54/2017/ND-CP dated May 08, 2017 of the Government of Vietnam providing
detailed regulations on some Articles and measures for implementation of
the Law on Pharmacy;
Pursuant to Decree No.
75/2017/ND-CP dated June 20, 2017 of the Government on function, tasks, powers
and organizational structures of the Ministry of Health of Vietnam;
At the request of the
Director General of Drug Administration of Vietnam,
The Minister of Health
promulgates a Circular on pharmaceutical products for which in vivo bioequivalence
studies are required and requirements for documentation of bioequivalence study
reporting during application for marketing authorization of these
pharmaceutical products in Vietnam.
Chapter
I
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Article
1. Scope
1. This Circular provides
for:
a) Generic drugs whose
active pharmaceutical ingredients (APIs) or dosage forms are subject to
bioequivalence study reporting during application for marketing authorization
in Vietnam;
b) Documentation of
bioequivalence study reporting of generic drugs.
2. This Circular applies
to generic drugs which have systemic actions after these drugs are absorbed
into the general circulation.
Article
2. Definitions
For the purposes of this
Circular, the terms below shall be construed as follows:
1. “reagent" is
a generic drug which is used for proving that it is therapeutically equivalent
(with respect to both efficacy and safety of the drug) to a comparator product
when being administered to patients in the same dose by the same route under
the specific conditions specified in the labeling (if any) via data of in vivo
bioequivalence studies or in vitro bioequivalence studies.
2. “comparator
product/reference product” is a pharmaceutical product with which the
generic drug is intended to be interchangeable in clinical practice. The
comparator products will normally be innovator pharmaceutical products or
products granted marketing authorizations for which efficacy, safety and
quality have been established.
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4. “pharmaceutical
equivalence” means products containing the same molar amount of the same
API (for single ingredient drugs) or the same APIs (for multi-ingredient drugs)
in the same dosage form, having the same drug release mechanism, the same route
of administration and the equivalent quality standards.
5. “Pharmaceutical
alternatives” are products which contain the same active pharmaceutical
moiety or moieties but differ in chemical form (e.g. different salts, esters,
ethers, isomers, mixtures of isomers, complexes or derivatives) of each API or
differ in drug content or dosage form.
6. “drug under
consideration" is a generic drug for which a marketing authorisation
application which includes documentation of bioequivalence study reporting has
been submitted.
7. “In vivo
bioequivalence study” means a clinical study undertaken on a volunteer and
designed to compare the bioavailability of a generic drug with a comparator
product with the aim of demonstrating the interchangeability of generic drugs
to replace comparator products.
8. “equivalence
dissolution” means a study that includes comparison of dissolution profile
between drugs/pharmaceutical products in different dissolution media.
Equivalence dissolution is also known as an in vitro equivalence study.
9. “In vitro - in vivo
correlation” means a predictive mathematical model describing the
relationship between the in vitro property (drug dissolution or release) and
relevant in vivo response (drug concentration or amount absorbed in biological
fluids) of a drug/pharmaceutical product.
10. “research
facility” is an organization partly or wholly participating in the in vivo
bioequivalence study or in vitro equivalence study of the drug under
consideration.
11. “immediate release
dosage form” means a dosage form using classic excipients and
preparation techniques, without intentionally changing the drug release rate
from the dosage form- including conventional dosage forms such as tablets,
capsules, suspensions, solutions for oral administration, solutions,
suspensions, emulsions for injection and unconventional dosage forms which are
also known as special dosage forms such as solid dispersion systems, lozenges,
chewable tablets, oral dispersible tablets and sublingual tablets.
12. “Modified release
dosage form” means a dosage form using some excipients and/or preparation
techniques different from those of the immediate release dosage form in order
to produce a rate and/or site of drug release different than those of the
immediate release dosage form when being administered by the same route. The
most common modified release dosage forms include delayed release, prolonged
release, multiphasic release, drug, intramuscular/subcutaneous depot and
transdermal drug delivery system.
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14. “Biopharmaceutics
classification system (BCS)” means a system of classifying APIs based upon
their aqueous solubility and intestinal permeability.
15. “bio-waiver” means
the approval for a generic drug, based on evidence of equivalence between the
generic drug and its comparator product other than in vivo bioequivalence study
reporting.
16. “study under
fasted condition” is a bioequivalence study that a volunteer participating
in the study did not eat and drink alcohol or xanthine for at least 8 hours
before taking the drug.
17. “study under fed
condition” is a bioequivalence study that a volunteer participating in the
study takes the drug immediately after eating or according to the instructions
on time for taking the drug compared to the time for eating as mentioned in the
drug property summary.
18. “single-dose
study” means a bioequivalence study that biological samples used for
analysis are collected after taking a single dose of drug at each study period.
19. “multi-dose study”
means a bioequivalence study that biological samples used for analysis are
collected after taking multiple doses of a drug to achieve a stable drug
concentration in the blood.
20. “Polarized
approach” means the analysis and selection of 02 strengths in many
different strengths of the same drug (with the same dosage form, manufactured
by the same manufacturer) that are determined as having the most significant
differences so that any difference between the remaining strengths is within
the difference of these two selected strengths to conduct a research and
extrapolate the research results to the remaining strengths.
21. “ASEAN" is
an abbreviation of the English phrase “Association of Southeast Asian Nations”,
translated into Vietnamese as “Hiệp hội các nước Đông Nam Á”.
22. “ICH” is an
abbreviation of the English phrase “International Conference on Harmonisation
of Technical Requirements for Registration of Pharmaceuticals for Human Use”,
translated into Vietnamese as “Hội nghị quốc tế về hài hòa các thủ tục đăng ký
dược phẩm sử dụng cho con người”.
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24. “Form of ICH
bioequivalence study reports" means a reporting form according to the
Guideline on the Structure and Content of Clinical Study Reports (E3 Guideline)
of ICH.
Chapter
II
REGULATORY REQUIREMENTS OF BIOEQUIVALENCE STUDY REPORTS FOR GENERIC
DRUGS CONTAINING APIS OR THOSE IN DOSAGE FORM
Article
3. Regulatory requirements of bioequivalence study reports for generic drugs
containing APIs upon applying for marketing authorization
1. Criteria for selection
of an API contained in a generic drug subject to a bioequivalence study report
upon applying for marketing authorization are sorted according to the following
priority:
a) Possessing a narrow
therapeutic index;
b) Having a
bioavailability that is low and/or very different between individuals;
c) Being presented in
prescription drugs, belonging to one of the drug classes including
cardiovascular drugs, hypoglycemic drugs, antibiotics,
antipsychotic/antiepileptic drugs, antivirals;
d) Being contained in
drugs in the list of drugs used in National Programs, including: HIV-AIDS
prevention project; Community mental health protection project; Tuberculosis
prevention project; Malaria Prevention Project.
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Article
4. Regulatory requirements of bioequivalence study reports for generic drugs in
dosage form upon applying for marketing authorization
Generic drugs in dosage
form for which reports on bioequivalence study data are required upon applying
for marketing authorization include:
1. Immediate release
pharmaceutical products with systemic action, which contain APIs specified in
Clause 2, Article 3 of this Circular and do not fall into the cases specified
in Article 5 of this Circular.
2. Modified release
pharmaceutical products with systemic action, except for cases specified in
Article 5 of this Circular.
Article
5. Generic drugs for which in vivo bioequivalence studies are waived due to the
available bioequivalence between these drugs and comparator products
Generic drugs for which
in vivo bioequivalence studies are waived due to the available bioequivalence
between these drugs and comparator products include:
1. Generic drugs which
are used for intravenous (IV) injection in the form of aqueous solutions,
contain the same APIs at the same molar concentrations when being used as
comparator drugs and do not contain excipients that interact with APIs or have
the same effect on the distribution of the APIs as that of the comparator
products. In case these excipients must be used in the formulation, these
excipients and excipients contained in the comparator products must have the
same qualitative and quantitative composition or if there is a difference in
quantity, it must be demonstrated that this difference does not affect the
pharmacokinetics of the APIs.
2. Generic drugs which
are used for other routes of administration other than IV injection in the form
of aqueous or oil-based solutions, contain the same APIs at the same molar
concentrations and contain the same excipients with the similar concentrations
when being compared with their comparator products. For an injecting drug which
is an aqueous solution, excipients in the formulation may be different but they
must have the same class (same effect) and concentration as those contained in
the comparator product and different excipients must not affect the viscosity
of the aqueous solution according to evidence.
3. Generic drugs which
are oral solutions (including solid dosage-form drugs with instructions for
dissolving into oral solutions before use), are equivalent in pharmaceutical
formulation to their comparator products and both generic drugs and comparator
products do not contain excipients which may affect the in vivo delivery,
absorption or stability of APIs as those in their comparator products. In
case there must have excipients that may affect the in vivo delivery,
absorption or stability of APIs in the pharmaceutical formulation of the
generic drugs, categories and quantities of these excipients of the generic
drugs must be equivalent to those of their comparator products.
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Chapter
III
REQUIREMENTS FOR COMPARATOR PRODUCTS AND IN VIVO BIOEQUIVALENCE
STUDIES
Article
6. Comparator products used in in vivo bioequivalence studies
1. Criteria for selection
of a comparator product for an in vivo bioequivalence study serving the
application for marketing authorisation are prescribed in the priority as
follows:
a) Being a
drug/pharmaceutical product on the list of proprietary drugs published by the
Ministry of Health or a pharmaceutical product granted a marketing
authorization with adequate data on clinical efficacy, safety and quality;
b) Being an innovator
pharmaceutical product which is not granted a Marketing Authorization Approval
certificate in Vietnam but is approved and marketed in a country by a stringent
pharmaceutical regulatory authority prescribed in clause 10 Article 2 of
Circular No. 32/2018/TT-BYT of the country;
c) In case it is unable
to determine any comparator product meeting regulations in point a and point b
of this clause, the comparator product will be selected in the priority as
follows:
- Being a pharmaceutical
product which is approved and marketed in a country by a stringent
pharmaceutical regulatory authority prescribed in clause 10 Article2 of
Circular No. 32/2018/TT-BYT of the country.
- Being a pharmaceutical
product which has been prequalified by the World Health Organization (WHO).
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2. In addition to the
requirements mentioned in clause 1 of this Article, if the comparator product
used in the in vivo bioequivalence study is a an immediate release
pharmaceutical product, modified release pharmaceutical product or fixed-dose
combination finished pharmaceutical product, it must meet the following
requirements as well:
a) In case a
pharmaceutical product which is under consideration is a single ingredient drug
in immediate release dosage form, the comparator product must be a single
ingredient drug in immediate release dosage form as well;
b) In case the
pharmaceutical product which is under consideration is a modified release
pharmaceutical product, the comparator product must also be a modified release
product with the same drug release mechanism as the pharmaceutical product;
c) For a fixed-dose
combination finished pharmaceutical product:
- In case the
pharmaceutical product is under consideration to intendedly replace a
fixed-dose combination finished pharmaceutical product approved with complete
documentation of safety and efficacy in clinical practice (which is a
proprietary drug or an innovator pharmaceutical product), the fixed-dose
combination finished pharmaceutical product will be selected to be the
comparator product.
- In case the
pharmaceutical product which is under consideration is developed for the
purpose of replacing the fixed-dose combination of single ingredient drugs with
complete documentation of safety and efficacy in clinical practice, the
comparator product will be a corresponding single-ingredient drug.
3. The comparator product
used in the in vivo bioequivalence study must have clear origin. Documentary
evidence of origin of the comparator product is prescribed in point c clause 1
Article 8 hereof.
4. On the basis of
criteria for selection of comparator products prescribed in clause 1 of this
Article, other requirements for them prescribed in clause 2 and clause 3 of
this Article and actual conditions, the Drug Administration of Vietnam shall
make a list of comparator products and ask the Consulting Council for issuance
of marketing authorizations of pharmaceutical products and medicinal
ingredients for promulgation of a Decision on issuing the List of comparator
products used in in vivo bioequivalence studies. The List of comparator
products used in in vivo bioequivalence studies is published on the website of
the Drug Administration of Vietnam at https://dav.gov.vn/.
Article
7. Regulations for bioequivalence studies in the documentation of
bioequivalence study reporting
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a) must be designed and
conducted according to the Guideline on conducting ASEAN bioequivalence studies
or reference guidelines of other organizations prescribed in Appendix VI
enclosed herewith.
b) For oral, modified
release pharmaceutical products with systemic action, must conduct the study
under fasted condition and fed condition;
c) For immediate release
pharmaceutical products with systemic action, except for cases specified in
Article 5 of this Circular, must conduct the study under fasted condition. On
the basis of pharmacokinetics of the comparator product, it is known that food
can affect bioavailability or the comparator product must be used after meal as
specified in instructions for use, may conduct the study under fed condition
instead of fasted condition;
d) For a fixed-dose
combination finished pharmaceutical product, must conduct the study on
bioequivalence evaluation of active pharmaceutical moieties contained in the
product;
dd) Apply in vivo
bioequivalence study design for each pharmaceutical product according to
recommendations of US Food and Drug Administration (US FDA) or European
Medicines Agency (EMA).
2. The study must be
conducted at testing centers that are evaluated and approved by competent
authorities in the hosting country and must comply with regulations on good
clinical practice (GCP) as prescribed in clause 1 Article 4 of Circular No.
29/2018/TT-BYT dated October 29, 2018 of the Ministry of Health on clinical
trials and good laboratory practice (GLP) as prescribed in clause 1 Article 3
of Circular No. 04/2018/TT-BYT dated February 09, 2018 of the Ministry of
Health on Good Laboratory Practice.
3. In case a
bioequivalence study of a pharmaceutical product which is under consideration
uses a comparator product which is an innovator pharmaceutical product but is
not produced in the same manufacturer as the innovator pharmaceutical product
granted a marketing authorization in Vietnam of the product, the applying
facility needs to prove the mutual interchangeability between the comparator
product used in the study and the innovator product granted the marketing
authorization in Vietnam of the product according to the ASEAN Guideline for
the conduct of Bioavailability/Bioequivalence studies.
4. Form of documentation
of bioequivalence study reporting of pharmaceutical products is prescribed in
point a clause 1 Article 8 hereof. Specific requirements for the
documentation of bioequivalence study reporting of pharmaceutical products
under consideration are prescribed in Appendix III enclosed herewith.
5. Bio-waiver is claimed
for pharmaceutical products under consideration if they meet the following
requirements:
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b) Pharmaceutical
products under consideration which have the same dosage form, pharmaceutical
formulation and manufacturing process as reagents in the bioequivalence studies
but differ in strengths of APIs meet regulations in section II Appendix II
enclosed herewith;
c) Oral, solid and
immediate-release pharmaceutical products under consideration which have
pharmaceutical equivalence upon being compare with comparator products and APIs
classified into the class of high solubility and high permeability according to
the biopharmaceutics classification system meet regulations in section III
Appendix II enclosed herewith;
d) Pharmaceutical
products under consideration which are manufactured a manufacturing site
different from it of reagents in a bioequivalence study meet requirements in
section IV Appendix II enclosed herewith.
Chapter
IV
DOCUMENTATION OF BIOEQUIVALENCE STUDY REPORTING
Article
8. Documentation of bioequivalence study reporting of pharmaceutical products
under consideration and comparator products.
1. The documentation
shall include:
a) A report on in vivo
bioequivalence study data based on the current form of ASEAN bioequivalence
study reports or form of ICH bioequivalence study reports, from which a written
commitment on the equivalence between the reagent in the study and the pharmaceutical
product under consideration must be prepared according to Schedule 01/BE
prescribed in Appendix VII enclosed herewith;
b) Documents and
information of the research facility as prescribed in Article 12 hereof;
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- A copy of an invoice of
comparator product with clear name and address of the manufacturer;
- A copy of the product
label with confirmation of the applying facility/manufacturer with full and
clear information about name of the comparator product, name and address of the
manufacturer, batch number and expiry date;
- The written commitment
with signature of the Director of the applying facility/manufacturer on the
purchase of the comparator product from the right country where the product is
granted its marketing authorisation approval certificate and preservation under
the reasonable condition labeled from the time of purchase to the time of
beginning conducting the study in order to confirm the authentication of the
documents provided above.
2. In case a volunteer
takes the pharmaceutical product under consideration in different conditions
(fed, fasted, single-dose or multi-dose), the documentation of bioequivalence
study reporting including various reports on bioequivalence studies and each of
them will specify each condition of taking the product must be adequate or
documented to have adequate documents prescribed in clause 1 hereof.
Article
9. Documentation of bioequivalence study reporting of pharmaceutical products
under consideration prescribed in point a point b clause 5 Article 7 hereof
The documentation of
bioequivalence study reporting of a pharmaceutical product under consideration
prescribed in point a point b clause 5 Article 7 hereof includes:
1. A petition for
bio-waiver for the pharmaceutical product under consideration according to
Schedule 02/BE prescribed in Appendix VII enclosed herewith.
2. A dossier on
bioequivalence of a strength or strengths selected to conduct an in vivo
bioequivalence study for the comparator product meeting regulations in Article
8 hereof.
3. Documentation of the
selection of strengths for bioequivalence study reporting and use of the result
of bioequivalence study of these strengths to apply bio-waiver for other strengths,
including strength of the pharmaceutical product under consideration.
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5. A comparison table for
manufacturing process with strengths for which the bio-waiver is applied,
including strength of the pharmaceutical product under consideration and that
of strengths of which there are bioequivalence study reports.
6. An in vitro
bioequivalence study report between strengths for which the bio-waiver is
applied, including strength of the pharmaceutical product under consideration
and strengths of which there are reports on bioequivalence study data.
Requirements for the in vitro bioequivalence study report are prescribed
specifically in Appendix IV enclosed with this Circular.
7. A commitment to the
equivalence between the pharmaceutical product under consideration and the
reagent used in in vitro bioequivalence study according to schedule 01/BE
prescribed in Appendix VII enclosed herewith.
8. Information about
linear pharmacokinetics of the pharmaceutical product under consideration (if
applicable).
Article
10. Documentation of bioequivalence study reporting of the pharmaceutical
products under consideration prescribed in point c clause 5 Article 7 hereof
The documentation of
bioequivalence study reporting of a pharmaceutical product under consideration
prescribed in point c clause 5 Article 7 hereof shall include:
1. A written petition for
bio-waiver for the pharmaceutical product under consideration according to
schedule 02/BE prescribed in Appendix VII enclosed herewith.
2. Documents of the
research facility prescribed in Article 12 hereof.
3. Documentary evidence
of the good solubility and permeability of the API/APIs contained in the
product under consideration according to the guideline in Appendix III. The
bio-waiver is based on the BCS of the ASEAN Guideline on conduct of
bioequivalence studies issued together with Circular No. 32/2018/TT-BYT .
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a) A comparison table for
excipients used in the formulation between the product under consideration and
the comparator product or a pharmaceutical product that is not a comparator
product but has the pharmaceutical equivalence between it and the product under
consideration and has been used as a reference product by one of the
stringent pharmaceutical regulatory authorities specified in Clause 10 Article
2 of Circular No. 32/2018/TT-BYT with information on reference sources for
excipients in the formulation of the comparator product or reference product..
Some official approved
reference sources include: the approved Guideline on use of pharmaceutical
products by the Drug Administration of Vietnam, overview of properties of
authorized pharmaceutical products or report on evaluation of pharmaceutical
products posted on the website of the European Medicines Agencies (EMA) and the
stringent regulatory authority (SRA) prescribed in clause 10 Article 2 of
Circular No. 32/2018/TT-BYT or on official sites for drug and medication information
such as eMC (electronic Medicines Compendium). In case information on the
excipients used in the formulation of the comparator product or reference
product can not be found, qualitative results of the excipients in the
formulation of the comparator product or the reference product must be provided
to demonstrate that the product under consideration has the same excipients in
the formulation as one of these products;
b) In case excipients
used in the formulation of the product under consideration affect
bioavailability of it, qualitative and quantities results of the excipients
used in the formulation of the product under consideration and that of the
comparator product must be provided to demonstrate that the product under
consideration has the same excipients as the comparator product;
c) A report on validation
of qualitative and quantitative analytical procedures used in the
above-mentioned studies.
5. A report on evaluation
of the solubility of the product under consideration (for products with the
very rapid solubility) or a report on in vitro bioequivalence study between the
product under consideration and the comparator product (for products with the
rapid solubility). Requirements for the report on in vitro bioequivalence study
are prescribed specifically in Appendix IV enclosed with this Circular.
6. A commitment of the
equivalence between the product under consideration and the reagent used in the
in vitro study or in vitro bioequivalence study according to schedule 01/BE
prescribed in Appendix VII enclosed herewith.
7. Related documents
concerning the comparator product in accordance with regulations in point c
clause 1 Article 8 hereof.
Article
11. Documentation of bioequivalence study reporting of pharmaceutical products
under consideration prescribed in point d clause 5 Article 7 hereof
The documentation of
bioequivalence study reporting of a pharmaceutical product under consideration
prescribed in point d clause 5 Article 7 hereof includes:
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2. In case of change of
manufacturing site due to the change from the manufacturer of the product owner
to a contract manufacturer of the product owner or change between contract
manufacturers of the product owner: a product owner's document about the
manufacturer of the product under consideration designated as the contract
manufacturer of the product owner, and a written agreement on participation in
manufacture of the product under contract of the designated contract
manufacturer. In case the manufacturing site is changed due to the change
from one contract manufacturer to another of the product owner, a product
owner's written explanation of reasons for this change shall be added.
3. In case of change of
manufacturing site due to the change between different manufacturers of the
same product owner or between different manufacturing sites of the same
manufacturer: a written explanation of the product owner or applying facility
of reasons for the change of manufacturing site.
4. A document about
quality of the reagent used in the bioequivalence study includes:
- Part S. APIs: an
overview of API integration process attached to a process mapping; Solvents
used in the process; API properties; Impurity properties; Quality standards of
APIs; Analytical data on batches of APIs;
- Part P. Finished
pharmaceutical products (FPPs): Pharmaceutical formulation; Manufacturing
process; Quality standards of excipients; Quality standards and analytical
procedures for FPPs; Analytical data on at least 03 pilot-scale batches of FPPs
as specified in Appendix V hereof - including batches used in in vivo
bioequivalence study; Stability of FPPs (in case there is not enough data on
the long-term stability of the product under consideration until its registered
expiry date); Bioequivalence dossiers satisfying the regulations in Article 8
hereof.
5. Documents prescribed
in clauses 3, 4, 5, 6, 7, and 8 Article 9 hereof in case the product under
consideration has been manufactured according to regulations in point a or b
clause 5 Article 7 hereof at the old manufacturing site.
6. A table listing
changes related to the pharmaceutical formulation, production batch size,
manufacturing process, manufacturer of APIs during marketing (if any) of the
pharmaceutical product under consideration manufactured at the old
manufacturing site.
7. A written approval for
these changes of the pharmacy authority of the host country.
8. A dossier on changes
and addition to each listed change meeting regulations in Appendix II enclosed
with Circular No. 32/2018/TT-BYT , except for administrative documents.
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a) The equivalence of
manufacturing formulation between the product under consideration and the
reagent used in the bioequivalence study or that of pharmaceutical formulation
between them meeting requirements prescribed in sections I and II of Appendix
II enclosed herewith in case the product under consideration manufactured at
the old manufacturing site is approved for bio-waiver according to regulations
in point a or point b clause 5 Article 7 hereof;
b) The equivalence of
quality standards of APIs including API properties known as having effects on
bioavailability of FPPs, quality standards of excipients, manufacturing process
and standard operating procedures, equipment used in manufacture and
environmental control in the manufacturing process, quality standards of FPPs;
c) Properties of
excipients effecting bioavailability of APIs used in the formulation;
d) Comparison of
analytical data of at least 03 pilot-scale batches as prescribed in Appendix V
hereof including batches of reagents used in the bioequivalence study and
batches of products under consideration.
10. The documentation of
in vitro bioequivalence between the pharmaceutical product manufactured at the
old manufacturing site and the product under consideration. Requirements for
the report on in vitro bioequivalence study are prescribed specifically in
Appendix IV enclosed with this Circular. This documentation is not required if
the change of manufacturing site only relates to one or a number of stages
including primary packaging without dosing, quality control, batch release and
secondary packaging.
11. The data
documentation of in vitro - in vivo correlation which has been established in
case of modified release pharmaceutical products. In case the change of
manufacturing site only affects one or a number of stages including primary
packaging after dosing, quality control, batch release and secondary packaging,
this documentation is not required.
12. In case manufacturing
site changes due to the change of the manufacturer and the product manufactured
at the old manufacturing site which has been granted the marketing
authorization in Vietnam according to ASEAN common technical dossier (ACTD) but
has not been released as a documented bioequivalent product: the documentation
of bioequivalence study reporting of the product manufactured at the old
manufacturing site which must meet regulations in Article 8 and the
documentation of bioequivalence study reporting of the product under
consideration which must meet regulations in clauses 1, 2, 3, 5, 6, 7, 8, 9, 10
and 11 of this Article.
13. In case manufacturing
site changes due to the change of the manufacturer and the product manufactured
at the old manufacturing site which has been released as a documented
bioequivalent product: the documentation of bioequivalence study reporting of
the product under consideration which must meet regulations in clauses 1, 2, 3,
5, 6, 7, 8, 9, 10 and 11 of this Article.
14. In case there is a
change in different manufacturing sites of the same manufacturer and product
manufactured at the old manufacturing site which has been granted the marketing
authorisation in Vietnam: based on the changes and addition of
pharmaco-chemical products already granted marketing authorizations specified
in Appendix II issued with Circular No. 32/2018/TT-BYT .
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1. Documents of the
research facilities are not mandatorily required for facilities performing in
vivo bioequivalence study in Vietnam which have been assessed by the Ministry
of Health and published on the list of facilities meeting requirements for
conducting in vivo bioequivalence studies of pharmaceutical products on the web
portal of the Ministry of Health and website of the Drug Administration of
Vietnam or facilities permitted in writing to conduct in vivo bioequivalence
studies of pharmaceutical products by the Ministry of Health.
2. Documentation for a
research facility certified by the World Health Organization and published on
the list of prequalified laboratories allowed to conduct in vivo bioequivalence
studies or a facility assessed and certified as being allowed to conduct in
vivo bioequivalence studies by one of pharmaceutical regulatory authorities
prescribed in clause 10 Article 2 of Circular No. 32/2018/TT-BYT or a facility
certified by a competent regulatory authority of one of the countries of the
ICH to conduct in vivo bioequivalence study or a facility named in the list of
facilities performing bioequivalence studies approved under the ASEAN mutual
recognition arrangements (MRAs) for bioequivalence study reports of
pharmaceutical products (posted on the ASEAN website) and other facilities
belonging to countries with which Vietnam has a recognition arrangement is one
of the following two types of:
a) An original or a copy
of a certificate of a facility meeting GCP and GLP or ISO/IEC 17025 or a
license/certificate/confirmation/notification granted to a facility performing
in vivo bioequivalence study by a competent authority of the host country or a
certificate/confirmation/notification of approval for conducting in vivo
bioequivalence study by a facility from a competent authority of the host
country;
b) A result after
self-searching a legal document prescribed in point a of this clause from the
English website of the agency granting the legal document attached to a
document providing information on reference links to the Drug Administration of
Vietnam in case of an electronic legal document, or lack of signature, name of
signatory or certificate seal of a competent state regulatory authority of the
country granting the legal document.
3. Documentation which
must be submitted of a research facility which is not prescribed in clause 1
and clause 2 of this Article is one of the following documents:
a) An original or a copy
of a license/certificate/confirmation/notification granted to a facility
performing in vivo bioequivalence study by a competent authority of the host
country or a certificate/confirmation/notification of approval for trial conduct
of in vivo bioequivalence study of a pharmaceutical product under consideration
by a facility from a competent authority of the host country;
b) An original or a copy
of a certificate of meeting GLP or certificate of meeting ISO/IEC 17025 to
perform an analysis of biological fluids granted to a facility participating in
the analytical stage by a regulatory authority of the host country and a
certificate of meeting GCP granted to a facility participating in the clinical
stage by a regulatory authority of the host country;
c) In case a research
facility cannot provide documents prescribed in point a or b of this clause due
to law of the host country which not provides for issuing these documents to
the research facility, the unit which applies for marketing authorization of
the product under consideration is required to provide documentary evidence of
the compliance with GCP and/or GLP including:
- Documentary evidence of
the compliance with GLP:
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+ An original or a copy
of a contract between the bioequivalence research facility and its donor and
subcontractors;
+ A list of inspections
by regulatory authorities or accreditation bodies over the last 3 years and the
most recent inspection report of the local regulatory authority.
- Documentary evidence of
the compliance with GCP:
+ An overall profile of a
center for bioequivalence studies and clinical research (CBSCR) demonstrating
full testing capacity for conducting bioequivalence studies of pharmaceutical
products;
+ An original or a copy
of a contract between the bioequivalence research facility and its donor and
subcontractors;
+ An original or a copy
of an inspection report of a national pharmaceutical regulatory authority or
WHO which has been made within 3 years;
+ An original or a copy
of a research supervision report by a donor or research organization for
studies under consideration.
4. Documents prescribed
in clause 2, points a and b clause 3 of this Article must satisfy the following
requirements:
a) Documents must be
valid during the study period. A document shall be effective for 03 years
from the date on which it is issued if the effective period is not clarified on
the document;
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5. Documents prescribed
in this Article must be given seals of approval by the applying facility. The
applying facility must be responsible before the law for the result after
self-searching of the facility specified in point b clause 2 of this Article
and the legitimacy and accuracy of the documents and information specified in
this Article.
Chapter
V
IMPLEMENTATION
CLAUSES
Article
13. Effect
1. This Circular comes
into force from November 01, 2022.
2. Circular No.
08/2010/TT-BYT dated April 26, 2010 of the Minister of Health providing for
Guideline on reports on bioavailability/bioequivalence study data in applying
for marketing authorisation of pharmaceutical products is null and void from
the date on which this Circular comes into force.
Article
14. Application route
1. From the date on which
this Circular comes into force, each facility applying for marketing
authorization of the following pharmaceutical products must submit the
documentation of bioequivalence study reporting when the facility submits an
application for issuance of marketing authorization of the pharmaceutical
products including:
a) Generic drugs which
are prepared in the immediate release dosage form and delayed release dosage
form, are single active ingredient or fixed-dose combination drugs, contain
APIs on the List of APIs in the formulation for which bioequivalence study
reports are required when applying for marketing authorization of these drugs;
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2. After 36 months from
the date on which this Circular comes into force, each applying facility must
submit a dossier on in vivo bioequivalence study when submitting the
application for issuance of marketing authorization of all delayed release
generic drugs, except for generic drugs prescribed in clause 1 of this Article.
3. After 48 months from
the date on which this Circular comes into force, each applying facility
granted marketing authorization of pharmaceutical products containing APIs or
being in dosage forms required of in vivo bioequivalence studies according to
regulations herein must be certified publically to have pharmaceutical products
which are bioequivalent after being documented. Procedures for public
certification of pharmaceutical products which are bioequivalent after being
documented are prescribed in the Circular on the application for marketing
authorization of drugs and medicinal materials.
Article
15. Transitional regulations
1. Bioequivalence study
reports in applications for issuance, change or addition of marketing
authorizations submitted before the date on which this Circular comes into
force shall continuously comply with regulations in Circular No. 08/2010/TT-BYT
dated April 26, 2010 of the Minister of Health providing for guideline on
reports on bioavailability/bioequivalence study data in applying for marketing
authorization of pharmaceutical products, except for the case that facilities
voluntarily comply with regulations herein.
2. For pharmaceutical
products of which marketing authorization applications are submitted before the
date on which this Circular comes into force: bioequivalence study reports are
not required of additional submission before the dates on which marketing
authorizations are granted; facilities applying for marketing authorization
must comply with regulations in clause 3 Article 14 after marketing
authorizations of pharmaceutical products are granted.
3. In case in vivo
bioequivalence studies or in vitro bioequivalence studies are conducted before
the date on which this Circlular comes into force, commitments of enterprises
to origins of comparator products used in these studies shall be approved
according to schedule 03/BE prescribed in Appendix VII enclosed herewith if
documentary evidence of origins of these comparator products cannot be provided
according to regulations in point c clause 1 Article 8 hereof.
4. In case in vivo
bioequivalence studies are conducted before the date on which this Circular
comes into force, research facilities, comparator products and study designs
shall be approved if pharmaceutical products under consideration have been
approved and marketed in countries by their stringent regulatory authorities
prescribed in clause 10 Article 2 of Circular No. 32/2018/TT-BYT .
5. In case in vivo
bioequivalence studies are conducted before the date on which this Circular
comes into force, except for cases prescribed in clause 3 of this Article,
comparator products that are selected in these studies shall be approved in one
of the following cases:
a) Comparator products
are prescribed in the lists of proprietary drugs issued by the Ministry of
Health in the study periods;
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c) Comparator products
are approved and marketed in countries by their EMAs and SRAs prescribed in
clause 10 Article 2 of Circular No. 32/2018/TT-BYT .
Article
16. Reference regulations
In case legislative
documents and regulations cited in this Circular are changed, added or replaced,
new legislative documents or cited regulations shall be applied.
Reference technical
guidelines prescribed in Appendix VI enclosed herewith shall be applied as
bases for consideration and assessment of dossiers on in vivo bioequivalence
studies. In case these guidelines have changes or updates, research facilities
are permitted to apply new versions of them.
Article
17. Responsibility for implementation
1. Drug Administration of
Vietnam is responsible for:
a) organizing guidance
and implementing regulations herein;
b) updating and
publishing the List of comparator products used in in vivo bioequivalence
studies issued by the Ministry of Health;
c) updating and
publishing the list of facilities conducting bioequivalence studies assessed
and approved by the Ministry of Health of Vietnam;
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3. Agencies,
organizations and individuals should report difficulties that arise during the
period of implementation of this Circular to the Ministry of Health (via the
Drug Administration of Vietnam) for consideration and settlement./.
PP. MINISTER
DEPUTY MINISTER
Do Xuan Tuyen
APPENDIX I
list of APIs
contained in generic drugs for which
bioequivalence study reports are required while applying for marketing authorization
of pharmaceutical products
(enclosed with Circular No. 07/2022/TT-BYT dated September 05, 2022 of the
Ministry of Health of Vietnam)
No.
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1
Amlodipin
2
Azithromycin
3
Carbamazepin
4
Cefixim
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Cefuroxim
Axetil
6
Clarithromycin
7
Glibenclamid
8
Gliclazid
9
Metformin
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Metoprolol
11
Nifedipin
12
Rifampicin
13
Amoxicilin
and acid clavulanic
14
Carvedilol
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Cefpodoxim
16
Ezetimibe
17
Irbesartan
18
Itraconazol
19
Risperidon
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Rosuvastatin
21
Simvastatin
22
Sulpirid
23
Sultamicillin
24
Telmisartan
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Valproat
natri
26
Fenofibrat
APPENDIX II
REQUIREMENTS FOR
BEING GRANTED APPROVAL FOR PHARMACEUTICAL PRODUCTS FOR WHICH IN VIVO
BIOEQUIVALENCE STUDIES MAY BE WAIVED
(enclosed with Circular No. 07/2022/TT-BYT dated September 05, 2022 of the
Ministry of Health of Vietnam)
I. In case drugs
under consideration and their test products have the same proportions in their
pharmaceutical formulations when conducting bioequivalence studies:
1. Proportional formulations mean
pharmaceutical formulations of different strengths of the same pharmaceutical
product (the same dosage form, the same manufacturer) that meet the following
requirements:
a) Regarding an immediate release
product: when pharmaceutical formulations of the product have the same APIs and
excipients (excluding coating components, capsule shells, colour agents,
flavours and preservatives not capable of altering the bioavailability of the
product) in the different strengths in the same proportions of all the
APIs and excipients or where the amount of an API in the dosage form is either
less than or equal to 5% of the weight of the dosage form, the total weight of
the dosage form remains similar for all strengths or only the amount of filler
is changed to account for the change in amount of API and the amounts of other
core excipients in the dosage form should be the same for the strengths
concerned. If the product is an encapsulated tablet, the weight of the dosage form
is calculated as that of the solid product covered by a film coating. If the
product is a capsule, the weight of the dosage form is calculated as that of
the pharmaceutical product covered by a capsule shell.
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- Regarding an enteric-coated
tablet: when pharmaceutical formulations of the tablet have the same APIs and
excipients (excluding colour agents, flavours and preservatives not capable of
altering the bioavailability of the product) in the different strengths in the
same proportions of all the APIs and excipients or where an API is either less
than or equal to 5% of the weight of the dosage form, the total weight of the
dosage form remains the similar for all strengths or only the amount of filler
is changed to account for the change in amount of API and the amounts of other
core excipients in the dosage form should be the same for the strengths
concerned, and the ratio of acid resistant coating weight/volume to
tablet surface area between tablets with different strengths (mg/cm2)
must be the same).
- Regarding a pharmaceutical
product which is a capsule containing enteric-coated beads: enteric-coated
beads are in the same type for all different strengths (manufactured with the
same manufacturing process) and the different strengths have been achieved
solely by means of adjusting the number (or weight) of beads containing the
API.
c) Regarding a prolonged-release
product:
- When there is a series of
strengths of a product that have the same API release mechanism and
pharmaceutical formulations of the product have the same APIs and excipients in
the different strengths in the same proportions of all the APIs and
excipients or where the amount of an API in the dosage form is either less than
or equal to 5% of the weight of the dosage form, only the amount of filler is
changed to account for the change in amount of API and the amounts of other
core excipients in the dosage form should be the same for the strengths
concerned. If the product is an encapsulated tablet, the weight of the dosage
form is calculated as that of the solid product covered by a film coating. If
the product is a capsule, the weight of the dosage form is calculated as that
of the pharmaceutical product covered by a capsule shell.
- Regarding a pharmaceutical
product which is a capsule containing prolonged-release beads:
prolonged-release beads are in the same type for all different strengths
(manufactured with the same manufacturing process) and the different strengths
have been achieved solely by means of adjusting the number (or weight) of beads
containing the API.
d) For a transdermal product, APIs
and excipients are the same for all different strengths, the strengths are
proportional to the effective surface area of the patch, and the lower dose
strengths can be considered as partial areas of the highest dose strength.
dd) Regarding a fixed-dose
combination finished pharmaceutical product, all the APIs contained in the
product must meet requirements for a series of strengths that can be considered
to be proportionally formulated. If an API is considered, the remaining APIs
are considered as excipients in the pharmaceutical formulation unless
scientific evidence can be provided to show that differences in combination
ratios for the remaining APIs are acceptable. For a bilayer tablet, each layer
can be considered independently.
2. If a pharmaceutical product
under consideration has a series of strengths that is proportionally formulated
according to regulations in clause 1 of this section, a bioequivalence study
report of one or both strength(s) that is (are) considered to carry the
greatest risk of not reaching bioequivalence in accordance with regulations in
clause 3 of this section can be applied for consideration for biowaiver for the
remaining strengths if the strengths above meet both requirements
below-mentioned:
a) Strengths in the series of the
pharmaceutical product for which a proposal for submission of bioequivalence
study reports are not involved are used in the same manufacturing process as
that of the strengths applied in the in vivo bioequivalence study.
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3. Strengths in the series of the
pharmaceutical product for which a bioequivalence study report is required to
be able to consider for biowaiver for the remaining strengths are selected for
the study as follows:
a) For a pharmaceutical product
exhibiting linear pharmacokinetics (proportional increase in extent of
absorption): a bioequivalence study report is required at a strength, usually
the highest strength (except for cases that a study with the highest strength
cannot be conducted for safety or tolerability reasons).
b) For a pharmaceutical product
exhibiting non-linear pharmacokinetics:
- For a pharmaceutical product with
a less-than-dose-proportional increase in extent of absorption with increasing
dose over the therapeutic dose range, a bioequivalence study should be
conducted on at least the highest strength.
- For a pharmaceutical product with
a less-than-dose-proportional increase in extent of absorption with increasing
dose over the therapeutic dose range not caused by limited solubility of the
API but due to saturation of uptake transporters and both its test product and
comparator product do not contain any excipients that may affect
gastrointestinal (GI) motility or transport proteins, a bioequivalence study
should be conducted on the lowest strength or a strength in the linear range.
- For a pharmaceutical product with
a less-than-dose-proportional increase in extent of absorption with increasing
dose due to limited solubility of the API, a bioequivalence study should be
conducted on both the highest strength and the lowest strength or a strength in
the linear range.
The lasted edition of the ASEAN
Guideline for the conduct of bioequivalence studies, section 3.1.6. Strength to
be evaluated is a reference source to consider other exceptions applicable to
the selection of strengths for which a bioequivalence study report is required
to be able to consider for biowaiver for the other strengths in each one of the
above cases.
c) Special cases:
- For depot-injection
pharmaceutical products administered via intramuscular/subcutaneous injection:
if different strengths are only achieved due to the difference in the total
volume of these products contained in a dosage unit (total volume of these
products injected), an in vivo bioequivalence study may be conducted at any
strength. In cases where it is unable to use doses over the therapeutic dose
range for conduct of studies in healthy volunteers for safety reasons, a report
on an in vivo bioequivalence study at a dose lower than the therapeutic dose.
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- For an prolonged-release product
containing multiple subunits which are homogeneous pellets: the product
contains the same type of prolonged-release pellets in different strengths
(manufactured with the same manufacturing process) and it has a proportional
formulation: a report on an in vivo bioequivalence study at the highest
strength or a strength that is considered to carry the greatest risk of not
reaching the bioequivalence may be required.
- For pharmaceutical products for
which reports on in vivo bioequivalence studies under both fasted and fed
conditions are required (the same regulations with those for oral
prolonged-release products) and their pharmacokinetics are non-linear resulting
in the conduct of in vivo bioequivalence studies in 02 different strengths to
apply for biowaiver for the remaining strengths, only reports on in vivo
bioequivalence studies under both fasted and fed conditions in a strength and
applications for biowaiver are necessary or reports on in vivo bioequivalence
studies under fasted condition or fed condition in the remaining strengths,
based on which condition is considered to be less sensitive for detecting the
inequivalence between test products and comparator products. Regulations in
clause 3 section II of this Appendix are reference sources for selection of
which condition is considered to be less sensitive and application for
biowaiver under this condition for the remaining strengths.
4. The similarity of the
dissolution profile of pharmaceutical products under consideration between
strengths proposed for biowaiver with those for which in vivo bioequivalence
study reports are involved is prescribed in regulations of Appendix I.
Dissolution testing and similarity of dissolution profiles - ASEAN Guideline
for the conduct of bioequivalence studies.
II.
Pharmaceutical products under consideration of which dosage form and
manufacturing process are similar but API strengths are different to test
products used in a bioequivalence study (based on polarized approaches):
1. If a pharmaceutical product with
different strengths (the same dosage form and manufacturer) does not meet
requirements for applying biowaiver for proportional formulations prescribed in
clause 1 and clause 2 section I of this Appendix due to one of two following
reasons:
- The product has the same API and
excipient compositions in its pharmaceutical formulations for the different
strengths but the combination ratio between these compositions does not meet
regulations in clause 1 section I of this Appendix;
- The dissolution profiles of the
pharmaceutical product between strengths for which a biowaiver is considered
and strengths used in the in vivo bioequivalence study is not similar to each
other, a report on in vivo bioequivalence studies for 02 strengths selected on
the basis of polarized approaches to apply biowaiver for the remaining
strengths of the product.
2. For a prolonged-release or
enteric-coated pharmaceutical product under consideration, upon applying
polarized approaches, a biowaiver is only considered when the product has the
same API release mechanism for all the different strengths and the same
excipients playing a role of controlling the API release of the dosage form
(for the prolonged-release pharmaceutical product) or has the same API
controlled-release coatings (for the enteric-coated pharmaceutical product).
3. For pharmaceutical products for
which in vivo bioequivalence studies performed under both fasted and fed
conditions are required (the same regulations with that for an oral
modified-release product), if a biowaiver based on polarized approaches is
applied, in vivo bioequivalence studies under fasted or fed condition at only
one of the two strengths selected for the studies, depending on the condition
which is considered to be less sensitive for detection of the inequivalence
between test products and comparator products, may be waived. To be specific:
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b) In case where the summary of
characteristics recommends intake of comparator products only in a fed state: a
biowaiver of the fasted study at only one of the strengths is considered.
III. Oral, solid
and immediate-release pharmaceutical products under consideration which are pharmaceutically
equivalent to comparator products and APIs classified into the class of high
solubility and high permeability based on the biopharmaceutics classification
system (BCS):
1. Oral, solid and
immediate-release generic products, which are pharmaceutically equivalent to
their comparator products which are products that are dispersed/dissolved in
the oral cavity but not absorbed in the oral cavity, are pharmaceutically
equivalent to their comparator products, contain APIs proved to have good solubility
and permeability (BCS class I), which are not among those with a narrow
therapeutic range, will be considered not to require in vivo bioequivalence
studies when applying for marketing authorization or when requesting to declare
a product that has been granted a marketing authorization as a product with
proven bioequivalence if the following proofs are provided:
a) The products under consideration
are very rapidly dissolving (more than 85% of APIs presented in a single dosage
unit are dissolved in environments in a pH between 1 and 6.8 in 15 minutes), or
the products under consideration are rapidly dissolving (more than 85% of APIs
presented in a single dosage unit are dissolved in environments in a pH between
1 and 6.8 in 30 minutes) and the dissolution profiles of the products under
consideration are similar to those of the comparator products in the tried
environments.
b) For excipients known to affect
drug bioavailability (manitol, sorbitol, surfactants, etc.): The qualitative
and quantitative composition of these excipients in the products under
consideration must be similar to that of the comparator products.
c) Other excipients in formulations
of the products under consideration are qualitatively similar to those of
products pharmaceutically equivalent to the products under consideration
approved in any of reference countries, or common excipients known to have
properties with amounts used in the formulations should be within the normal
range suitable for dosage forms of the products under consideration.
2. Requirements for consideration
of a biowaiver based on the BCS specified in clause 1 of this section may also,
in lieu of the requirements for having pharmaceutical equivalence, apply to the
cases that both products under consideration and comparator products are
pharmaceutical alternatives but differ only in salt forms of APIs that
are highly soluble and permeable (BCS class I). A BCS-based biowaiver is not
applied when APIs used between the products under consideration and comparator
products differ in form of ester, ether, isomer or mixture of isomers,
complexes or other derivatives.
3. For fixed-dose combination
pharmaceutical products, a biowaiver may be considered based on the BCS if all
APIs in the formulations are highly soluble and permeable (BCS class I), the
excipients in the formulations of the products under consideration meet the
regulations mentioned at points b and c clause 1 of this section and the
solubility of the products under consideration, for each API
in the products, all meet the requirements specified at Point a, Clause 1 of
this Section.
4. Sublingual pharmaceutical
products, buccal troches and modified-release pharmaceutical products are
products for which a BCS-based biowaiver is not considered.
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6. Methods for evaluation of
solubility of the products under consideration and establishment of an in vitro
bioequivalence between the products under consideration and the comparator
products are prescribed in section IV. Finished pharmaceutical products (FPPs)
- Appendix III. BCS-based biowaiver - The lasted edition of the ASEAN Guideline
for the conduct of bioequivalence studies.
IV.
Pharmaceutical products under consideration manufactured in manufacturing sites
other than those of test products in bioequivalence studies:
1. These differences in manufacturing
sites are due to:
- Change from manufacturers of the
product owners to new contract manufacturers of the product owners or change
from these contract manufacturers of the product owners to other contract
manufacturers of the product owners, or
- Change between different
manufacturing sites of the same manufacturer.
2. For pharmaceutical products
manufactured abroad: both products manufactured in the old manufacturing sites
and products under consideration must be authorized for marketing in their host
countries by one of pharmacy authorities belonging to the stringent regulatory
authorities (SRAs).
3. Pharmaceutical products under
consideration must be similar to those manufactured in the old manufacturing
sites in terms of:
- Dosage forms;
- Quality standards of APIs,
including qualitative properties of APIs known to affect bioavailability of
FPPs;
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- Manufacturing processes and
standard operating procedures (SOPs);
- Equipment employed in the
manufacture of pharmaceutical products;
- Environmental conditions in the
manufacturing processes;
- Quality standards of FPPs.
4. Dissolution profiles of
pharmaceutical products under consideration must be similar to those of
pharmaceutical products manufactured in the old manufacturing sites. Methods
for establishment of similarity of the dissolution profiles between
pharmaceutical products under consideration and pharmaceutical products
manufactured in the old manufacturing sites are prescribed in Appendix I.
Dissolution testing and similarity of dissolution profiles - ASEAN Guideline
for the conduct of bioequivalence studies.
5. Besides the above requirements,
modified-release pharmaceutical products must be products for which an in
vivo-in vitro correlation is able to be established.
6. Requirements 4 and 5 shall be
exempted where the difference in manufacturing sites only affects one or a
number of stages including primary packaging without drug dosing (for example:
primary packaging of tablet and capsule dosage forms), quality control, batch
release and secondary packaging.
APPENDIX III
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I. Regarding
immediate-release products
1. Bioequivalence study reports
must be in accordance with the latest edition of the ASEAN Guideline for the conduct
of bioequivalence studies or other equivalent technical guidelines of EMA or
US-FDA.
2. Regarding oral pharmaceutical
products:
2.1. If the summary of
characteristics clearly recommends intake of comparator products only in a
fasted state or does not recommend the intake in a fed state or even in a fed
state, in vivo bioequivalence study reports of fasted studies are required.
2.2. If the summary of
characteristics clearly recommends intake of comparator products only in a
fasted state or does not recommend the intake in a fed state or even in a fed
state, in vivo bioequivalence study reports of fasted state studies are
required.
2.3. For pharmaceutical products
with specific formulations characteristics such as solid dispersions,
micro-emulsions, if the summary of characteristics does not recommends
intake of comparator products in a fasted state or a fed state (both fasted and
fed conditions may be recommended), reports on in vivo bioequivalence studies
performed under both fasted and fed conditions are required.
3. For pharmaceutical products
dispersed/dissolved in the oral cavity:
3.1. Regarding pharmaceutical
products under consideration which are pharmaceutically equivalent to
comparator products:
a) When comparator products may be
administered both with water and without water, reports on in vivo
bioequivalence studies performed between test products and comparator products
administered without water (that is a dosing condition carrying greater risks
of not achieving bioequivalence) are required.
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3.2. Regarding products under
consideration which are intended for replacing orally immediate-release
comparator products (if the products under consideration are pharmaceutical
alternatives of the comparator products):
Reports on in vivo bioequivalence
studies performed between test products administered both with water and
without water and comparator products administered with water or reports on in
vivo bioequivalence studies performed between test products administered without
water and comparator products administered with water are required.
II. For
modified-release pharmaceutical products
1. Regarding modified-release
pharmaceutical products under consideration which are designed for a purpose of
achieving API release rates similar to those of the comparator products:
1.1. In vivo bioequivalence study
reports must be suitable for the latest edition of the Guideline on the
pharmacokinetic and clinical evaluation of modified release dosage form of EMA
- Abridged application for modified release forms reffering to a marketed
modified release form.
1.2. Other specific notes:
a) Except for enteric-coated
products, in addition to single-dose studies, multiple-dose studies may be
considered for modified-release dosage forms with a tendency to accumulate
(e.g. after a single dose of the highest strength the AUC for the dosing
interval covers < 90% of AUC extrapolated to infinity/ rate of AUC (0-ԏ)/AUC
(0-ꝏ) < 90%).
b) For modified-release products
based on a multiphase release mechanism (two-phase release, rhythmic release):
in vivo bioequivalence study reports must prove that the test products are
bioequivalent to the comparator products in all phases.
c) For oral, modified-release
products: in vivo bioequivalence study reports must prove that test products
are bioequivalent to comparator products even when these products are taken in
a fasted or fed state.
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2. Regarding modified-release
products under consideration with API release rates different from those of
comparator products:
- Since bioequivalence between the
products under consideration and the comparator products cannot be established
due to differences in the API release rates, in lieu of in vivo bioequivalence
study reports, reports on pharmacokinetic studies of the products under
consideration, enclosed with reports on clinical safety and efficacy comparison
studies performed between the immediate-release products under consideration
and the immediate-release comparator products.
- The reports on pharmacokinetic
studies of the products under consideration and reports on safety and efficacy
comparison studies performed between the immediate-release products under
consideration and the immediate-release comparator products should be in
accordance with the latest edition of the Guideline on the pharmacokinetic and
clinical evaluation of modified release dosage form of EMA - Application for
modified release formulation of a drug that is authorized in a formulation with
a different release rate.
APPENDIX IV
GENERAL REQUIREMENTS FOR IN VITRO BIOEQUIVALENCE STUDy reports
(enclosed with Circular No. 07/2022/TT-BYT dated September 05, 2022 of the
Ministry of Health of Vietnam)
1. In vitro equivalence study
reports must demonstrate the similarity of the dissolution profiles between
test products and comparator products, under defined test conditions, typically
in at least three solvents: pH 1,2; pH 4,5 and pH 6,8. In case of not providing
enough test data in all 03 of these solvents or providing test data at other
pHs of solvents, there must be an explanation of the appropriateness of
omitting any solvent or using a solvent with a different pH in the test.
2. Profile compositions of an in
vitro bioequivalence study report include:
a) Test outline;
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- Information on test samples, test
conditions, test methods, test periods and performing locations.
- Data tables,
- Dissolution profiles,
- Statistical analysis,
- Resulting discussion.
c) Report on study data of
validation of the analytical procedure used in the test (enclosed with original
monitoring data representing the validation results).
APPENDIX V
Regulations on
pilot batch sizes
(enclosed with Circular No. 07/2022/TT-BYT dated September 05, 2022 of the
Ministry of Health of Vietnam)
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1. For immediate-release
tablets/capsules or modified-release tablets/capsules: At least 1/10 of
registered batch size or 100.000 dosage units, whichever is greater. In case
the registered batch size is less than 100.000 dosage units, the pilot batch
size must be equal to the registered batch size.
2. For powders, solutions,
suspensions: At least 1/10 of the largest registered batch size.
3. For injectable drugs including
solutions, powders/ lyophilized powders for injection, suspensions, emulsions:
At least 1/10 of the largest registered batch size or 50 liters (for liquid
drugs with a volume of 01 smallest packing unit which is greater than 2ml) and
30 liters (for liquid drugs with a volume of 01 smallest packing unit which is
equal to or less than 2ml), whichever is greater. In case of registering
multiple packing specifications with different volumes in 01 packing unit: the
minimum or 1/10 of the largest registered batch size or 50 liters, whichever is
greater.
4. Transdermal Therapy System: At
least 1/10 of registered batch size or 25.000 units, whichever is greater.
APPENDIX VI
Reference
Technical Guidelines (*)
(issued together with Circular No. 07/2022/TT-BYT dated September 05, 2022
of the Ministry of Health of Vietnam)
1. ASEAN Guideline for the conduct
of bioequivalence studies - 2015 Edition
2. ASEAN Variation Guideline for
Pharmaceutical Products – 2014.
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4. General Considerations for
Clinical Trials- ICH Topic E8, CPMP/ICH/291/95
5. Guideline for Good Clinical
Practice- (ICH E6 (R1), CPMP/ICH/135/95
6. Statistical Principles for
Clinical Trials- ICH E9, CPMP/ICH/363/96
7. Guideline on Bioanalytical
Method Validation- EMEA/CHPM/EWP/192217/2009
8. Guideline on the Pharmacokinetic
and Clinical Evaluation of Modified Release Dosage Forms (EMA/CPMP/EWP/280/96
Corr1).
9. Multisource (generic) pharmaceutical
products: Guidelines on registration requirements to establish
interchangeability -WHO Technical Reports Series, No. 992, Annex 7 (2015). 10.
USFDA: Product-Specific Guidances for Generic Drug Development
11. USFDA: Guidance for Industry:
Food-Effect Bioavailability and Fed Bioequivalence Studies
12. USFDA: Guidance for industry:
Statistical Approaches to Establishing Bioequivalence
13. USFDA: Guidance for industry:
Immediate-Release Solid Oral Dosage Forms: Scale-Up and Post-Approval Changes:
Chemistry, Manufacturing and Controls, In Vitro Dissolution Testing, and In
Vivo Bioequivalence Documentation (SUPAC-IR).
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15. EMA: Guideline on the
investigation of bioequivalence (European Medicines Agency, London, 20 January
2010, CPMP/EWWP/QWP/1401/98 Rev 1).
16. EMA: Guidance on classification
of minor changes of class IA, class IB and big changes of class II.
17. ICH HARMONISED GUIDELINE:
BIOPHARMACEUTICS CLASSIFICATION SYSTEM-BASED BIOWAIVERS, Topic M9, 2019
(*) Latest editions of the
above-mentioned Guidelines/Guidance will be updated for replacing the existing
editions mentioned in this Appendix.
APPENDIX III
FORMS
(issued together with Circular No. 07/2022/TT-BYT dated September 05, 2022
of the Ministry of Health of Vietnam)
FORM NO.
01/BE
COMMITMENT
ON SIMILARITY BETWEEN REGISTERED PHARMACEUTICAL PRODUCTS (*) AND TEST PRODUCTS
USED IN IN VIVO BIOEQUIVALENCE STUDIES
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We are:
Authorization holder………(full
name as presented in the establishment license)
Address…………. (full address
as presented in the establishment license).
And manufacturer……….. (full name
as presented in legal documents enclosed with the application)
Address............(full address
as presented in legal documents enclosed with the application)
We are together responsible for the
test product used in the in vivo bioequivalence study/in vitro bioequivalence
study No……(Study code/testing code) which is performed in..... (full
name and address of the facility at which the study/ testing method employed) in
the period from ….[date]… to ……[date]….. to be applicable to replace registered
pharmaceutical product/product proposed for publication of proven
bioequivalence with the name ……… (pharmaceutical product’s name/strength),
with the following specific information:
Comparison
content
Similarity
(1)
Difference
(1)
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- A pharmaceutical formulation
for 01 dosage unit:
Ingredients
Amount of ingredients
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- Manufacturing process,
including equipment employed in the manufacture of pharmaceutical products.
- Batch size
Detailed table of differences between
the test product used in the study and the pharmaceutical product under
consideration/ registered product/ product proposed for publication of proven
bioequivalence (2)
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Test
product used in the study
Registered
product/ product proposed for publication of proven bioequivalence
Attached
documents (3)
Manufacturing site
A pharmaceutical formulation for
01 dosage unit:
- Ingredients
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- Quality standards of
ingredients
Manufacturing process (including
equipment employed in the manufacture of pharmaceutical products)
Batch size (4)
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(1) Give a cross mark “X” in the
suitable checkbox
(2) Apply when there is a
difference between two products
(3) List attached documents
proving the differences between the test product used in the study and the
registered product that do not affect the replacement for the registered
product of the test product.
(4) Do not require attached
documents when batch size of the test product used in the in vivo
bioequivalence study in comparison with batch size of the product under
consideration meets the regulations in Appendix V of this Circular.
(*) In case of application for
point d clause 5 Article 7 of this Circular, the registered product may be
replaced by the product granted Certificate of pharmaceutical product (CPP).
We will be responsible for the
reliability of such information.
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,
date….month…year…..
Legal representative of the manufacturer
(direct signature, title, full name and seal)
FORM NO.
02/BE
Application
for A biowaiver
A. detailed information about the authorization holder and manufacturer
Authorization holder:
Address:
Manufacturer (1):
Address:
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An application for the biowaiver
(in vivo) is eligible for: (give a cross mark in the responding checkbox)
a) Pharmaceutical product eligible
for biowaiver (in vivo) for proportional formulations
b) Pharmaceutical product
eligible for biowaiver (in vivo) based on a polarized approach
c) Pharmaceutical product
eligible for BCS-based biowaiver (in vivo)
d) Pharmaceutical product
eligible for biowaiver (in vivo) when a product under consideration
manufactured in a manufacturing site other than that of the test product used
in an in vivo bioequivalence study.
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- Name:…… (trade name of the
product)
- Number of the marketing
authorization: (if it is a product granted a marketing authorization)
- Dosage form:
- API/API strength contained in 01
usage unit:
C. Information about the test product used in the in vivo
bioequivalence study (when having a request for applying cases a,
b and d)
- Name:…… (trade name of the product)
- Number of the marketing
authorization (2):
- Manufacturer (listing
manufacturers participating in the manufacturing process)
Name
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Position
D. List of Attached documents:
(attached to a copy of the
Official Dispatch presenting the consent of the Drug Administration of Vietnam
for the product granted the marketing authorization)
DD. COMMITMENT:
We are, including an authorization
holder and a manufacturer, together responsible for the inspection and seal in
terms of related parts in the documents enclosed with this application and the
reliability of such documents. We will wholly be responsible for any
falsification which is detected and penalized according to regulations of law.
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,
date….month…year…..
Legal representative of the manufacturer
(direct signature, title, full name and seal)
(1) clarify name of the manufacturer/manufacturer
participating in the manufacturing process of dosage forms of non-sterile
drugs; or manufacturer creating dosage forms and their secondary packaging for
sterile drugs.
(2): apply in case the test
product used in the in vivo bioequivalence study publicized to be a product
with proven bioequivalence.
FORM NO.
03/BE
Commitment
on origin of the comparator product used in the in vivo bioequivalence study
To: Drug Administration of
Vietnam – Ministry of Health of Vietnam
We are:
Authorization holder………(full name
as presented in its establishment license)
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And manufacturer ………..(full name as
presented in legal documents enclosed with the application)
Address…………. (full address as
presented in legal documents enclosed with the application)
We are together responsible for the
authentication of the following information related to the comparator product
used in the in vivo bioequivalence study/in vitro bioequivalence study No……(Study
code/testing code) which is performed in..... (full name and address of
the facility at which the study/ testing method employed) in the period
from ….[date]… to ……[date]….. :
Content
Information
Name
Manufacturer (manufacturing
address)
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Batch number
Expiry date
Attached documentation (if any)
Attached documentation (if any) (*):
…………………………….
(*) oblige to be involved for
studies performed before the effective date of this Circular.
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The above-mentioned comparator
product transferred and preserved under product’s preservation conditions
labeled from the date of purchase to the date of beginning of performing the
study.
We will be responsible for the
reliability of such information. We will wholly be responsible for any
falsification which is detected and penalized according to regulations of law.
Legal representative of the authorization holder
(direct signature, title, full name and seal)
,
date….month…year…..
Legal representative of the manufacturer
(direct signature, title, full name and seal)